Bisphosphonate-related osteonecrosis of the jaw (BRONJ), the presence of exposed bone in the oral cavity with current/previous bisphosphonate treatment and without prior exposure to radiation, has emerged as a significant clinical problem with broad health implications. The highest incidence rate of BRONJ exists in cancer patients and several key risk factors have been identified including bisphosphonate dose, presence of infection, and dental interventions. Cancer patients are treated with 10 times higher bisphosphonate doses than osteoporosis patients and there is a clear dose-dependent relationship to BRONJ. Immunosuppression, common among cancer patients, is implicated in the pathophysiology of BRONJ as numerous bacterial strains are found within these exposed lesions. Invasive dental procedures increase the risk of BRONJ by 10-fold and over 75% of all BRONJ cases are precipitated by some form of dental intervention. In a preclinical model our laboratory has shown the existence of necrotic bone matrix within the mandible (as opposed to the presence of exposed bone as seen clinically with BRONJ) following bisphosphonate-treatment. We hypothesize these regions of bone matrix necrosis within the mandible, which are clearly void of viable osteocytes and have disrupted canalicular networks, represent a precursor to BRONJ. The goal of this proposal is to determine if a connection exists between this matrix necrosis and the BRONJ (exposed bone in the oral cavity). In Aim 1 we will measure osteocyte viability (lactate dehydrogenase histochemistry;LDH), osteocyte apoptosis (caspase-3 immunohistochemistry) and canalicular network integrity (basic fuchsin staining) in mandible samples from patients with and without with BRONJ, as well as age/sex matched cadaver controls. In Aim 2 we will combine high doses of intravenous bisphosphonates, immunosuppressive therapy, and dental extraction in a canine model to determine if a link exists between bisphosphonate-induced matrix necrosis and manifestation of exposed oral bone lesions (clinical BRONJ). Aim 2 will utilize similar histological outcomes as Aim 1 at both extraction and non-extraction sites, as well as additional outcome measures related to bone healing (bone volume, vascularity). The results of this study will significantly advance our understanding of the effect of bisphosphonates on the bones of the oral cavity. If our hypothesis is correct these data would break new ground in our understanding of BRONJ pathophysiology and provide a new model system for future studies of this condition. PUBLIC HEALTH RELEVANCE: Bisphosphonates, a common class of drug used for cancer treatment and osteoporosis, are associated with a condition known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study will assess matrix necrosis and loss of osteocyte viability in clinical BRONJ samples and determine whether these changes can be recapitulated in a preclinical model. The results of this project have the potential to break new ground in our understanding of BRONJ pathophysiology and provide a new model system for future studies of this condition.